An Efficient High-Dimensional Gene Selection Approach based on Binary Horse Herd Optimization Algorithm for Biological Data Classification

The Horse Herd Optimization Algorithm (HOA) is a new meta-heuristic algorithm based on the behaviors of horses at different ages. The HOA was introduced recently to solve complex and high-dimensional problems. This paper proposes a binary version of the Horse Herd Optimization Algorithm (BHOA) in order to solve discrete problems and select prominent feature subsets. Moreover, this study provides a novel hybrid feature selection framework based on the BHOA and a minimum Redundancy Maximum Relevance (MRMR) filter method. This hybrid feature selection, which is more computationally efficient, produces a beneficial subset of relevant and informative features. Since feature selection is a binary problem, we have applied a new Transfer Function (TF), called X-shape TF, which transforms continuous problems into binary search spaces. Furthermore, the Support Vector Machine (SVM) is utilized to examine the efficiency of the proposed method on ten microarray datasets, namely Lymphoma, Prostate, Brain-1, DLBCL, SRBCT, Leukemia, Ovarian, Colon, Lung, and MLL. In comparison to other state-of-the-art, such as the Gray Wolf (GW), Particle Swarm Optimization (PSO), and Genetic Algorithm (GA), the proposed hybrid method (MRMR-BHOA) demonstrates superior performance in terms of accuracy and minimum selected features. Also, experimental results prove that the X-Shaped BHOA approach outperforms others methods

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

A Biophysical Study of Fluoroacetate Dehalogenase

Fluoroacetate dehalogenase (FAcD) is a homodimeric enzyme and belongs to the a/Ă hydrolase protein superfamily. It possesses the ability to cleave C-F bonds and so is capable of using the simplest fluorocarbon, fluoroacetate, as its main source of carbon. The underlying mechanistic details that allow this enzyme to perform C-F cleavage are still unknown. However, details into building a mechanistic model for the type of asymmetric cooperative behavior observed in FAcD are slowly being revealed. In the following studies, I use FAcD as a model system to study its catalytic reaction mechanism focusing on the enzymatic coordinate pathway and the dynamics of various states along the pathway. As well, I use FAcD as a suitable choice to study irreversible enzymatic reactions via time-resolved crystallography (TRX) experiments. Using a series of biophysical techniques I analyze structure, function, and dynamics of both the ground state and transient higher energy states. It was demonstrated using X-ray crystallography that there is subtle structural asymmetry between the individual subunits in the apo state of the enzyme. This asymmetry becomes more pronounced during catalytic activity whereby entropic loss from substrate binding in one protomer is compensated by an increase of entropy and a loss of structural waters in the other. Kinetic measurements of FAcD revealed that during titrations involving excess substrate the enzyme undergoes substrate inhibition. Biphasic chemical shifts identified by NMR indicated a secondary binding site, which was confirmed via crystal structures of various complexes of a catalytically slow mutant (Y219F). This secondary binding site decreases transmission along the allosteric pathway, which could be mapped using rigidity-based transmission allostery (RTA) analysis. Using FAcD as a model system for method development I applied fixed target approaches for time-resolved crystallography (TRX). Using light activation of a caged-substrate, I could verify that structural asymmetry first observed using a series of mutants is still conserved. As well, structural features of the active site and cap domain change from one time-point to the next and corroborate previous results. Taken together, this data shows nuanced mechanistic insights into the structural enzymology of a homodimeric enzyme.Ph.D.2019-12-19 00:00:0

Can we sustain success in reducing deaths to extreme weather in a hotter world?

In an incredible story of human adaptation, the aggregate global risk of mortality to extreme weather declined by over two orders of magnitude over the past century. Yet the data show that large losses of lives to extreme weather disasters persist in nations typified by poor economic development, weak institutions, and political instability. And currently we are seeing spikes in mortality from extreme heat events in rich nations, including a wave of new reported deaths in Japan, Europe, and Canada during 2018. These events and future projections of increasing exposure suggest that we need to revisit adaptation strategies to deal with the adverse effects of extreme weather disasters across the world.Arts, Faculty ofScience, Faculty ofOther UBCNon UBCGeography, Department ofLiu Institute for Global IssuesResources, Environment and Sustainability (IRES), Institute forReviewedFacultyResearche

Time-resolved crystallography reveals allosteric communication aligned with molecular breathing

A comprehensive understanding of protein function demands correlating structure and dynamic changes. Using time-resolved serial synchrotron crystallography, we visualized half-of-the-sites reactivity and correlated molecular-breathing motions in the enzyme fluoroacetate dehalogenase. Eighteen time points from 30 milliseconds to 30 seconds cover four turnover cycles of the irreversible reaction. They reveal sequential substrate binding, covalent-intermediate formation, setup of a hydrolytic water molecule, and product release. Small structural changes of the protein mold and variations in the number and placement of water molecules accompany the various chemical steps of catalysis. Triggered by enzyme-ligand interactions, these repetitive changes in the protein framework’s dynamics and entropy constitute crucial components of the catalytic machinery

Deamidation of the human eye lens protein γS-crystallin accelerates oxidative aging

Cataract, a clouding of the eye lens from protein precipitation, affects millions of people every year. The lens proteins, the crystallins, show extensive post-translational modifications (PTMs) in cataractous lenses. The most common PTMs, deamidation and oxidation, promote crystallin aggregation; however, it is not clear precisely how these PTMs contribute to crystallin insolubilization. Here, we report six crystal structures of the lens protein γS-crystallin (γS): one of the wild-type and five of deamidated γS variants, from three to nine deamidation sites, after sample aging. The deamidation mutations do not change the overall fold of γS; however, increasing deamidation leads to accelerated disulfide-bond formation. Addition of deamidated sites progressively destabilized protein structure, and the deamidated variants display an increased propensity for aggregation. These results suggest that the deamidated variants are useful as models for accelerated aging; the structural changes observed provide support for redox activity of γS-crystallin in the lens